Carrie Partch: Stop the clocks - when circadian genes go wrong
Professor Carrie Partch, image courtesy of Carrie Partch
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As Priya just mentioned, small genetic differences can explain why some people are able to get up and go out for a run, meditate and cook a full breakfast before I’ve even woken up in the morning. Meanwhile I’m wired all the way up til midnight when everyone else has gone to bed.
But some people have genetic disorders that cause much bigger shifts in their circadian rhythms. One researcher who is looking into these is Professor Carrie Partch, a biophysicist at UC Santa Cruz, so I asked her how you go about studying these clock genes in cells. And just so you know, Carrie has a motor neurone disease that affects her speech, so she’s using an AI clone of her own voice to answer my questions - isn’t technology amazing!
Sally: How do you actually study the molecular biology of circadian rhythms? Can you look at a cell and see the different stages in the cycle? Or is it all computer models?
Carrie: We can actually study these rhythms in cells and watch the clock tick. To do this, we borrow the luciferase gene that makes fireflies glow, and we attach it to the end of the clock gene, Per2, so that the cells emit light when PER2 protein is present at night time, and they fall dark when the protein is gone by the morning.
Carrie: It's really beautiful. You can watch these movies of cells giving off a pulse of light every evening for days on end. Using these glowy cells to report on clock timing, we then begin to probe the function of other clock genes by making mutations in the DNA to test how the parts of this biological clock work together in the cell.
Carrie: As biochemists, we're interested in the molecular details of how these clock proteins fit together and how inherited changes to them alters the clock. Sometimes we study these proteins outside the cell in test tubes so we can solve their structures and actually see how they fit together at the atomic level.
Carrie: This helps us identify steps in the molecular clock that are important for timekeeping and come up with new strategies for potentially controlling the clock with drugs.
Sally: Why don’t we have a drug for jet lag yet?
Carrie: You know, I'm not quite sure. It's probably that jet lag seems like an insignificant health problem, or a first-world problem brought on by the choice to travel, but a drug that could help us speed up our ability to synchronise internal biological clocks to a mismatched light-dark environment could have incredible benefits for shift workers who routinely fight their clocks to be alert at night.
Carrie: The World Health Organisation listed shift work as a probable carcinogen because of the disruption of circadian rhythms that comes from bouncing back and forth between day and night shifts. There's been some exciting work recently identifying natural products that help animal models shift their clocks much faster to simulated travel or some that fortify their biological clocks to improve health on higher fat western diets and throughout ageing.
Carrie: With recent advances in our understanding of druggable targets in the clock, I'm incredibly optimistic that one day we'll have the ability to leverage our circadian rhythms to improve our overall health and well being.
Sally: We’ve just heard from Priya how different individuals have small variations in their clock genes that make them more likely to be a morning lark or a night owl, but you’re interested in the bigger genetic disorders. What happens when someone’s clock genes go wrong?
Carrie: When people have genetic disorders related to circadian rhythms, they manifest as sleep phase disorders that significantly advance or delay bedtimes, giving rise to extreme morning lark or night owl behaviour. It turns out that folks with these sleep phase disorders that manifest as extreme morning larks or night owls often tend to have other issues, like migraines, mood disorders, and hormone dysregulation.
Carrie: With advances in human genetics, scientists like Louis Ptacek and Ying-Hui Fu at UCSF have been able to pinpoint inherited changes in several different clock genes and begin to identify why these families have a tendency to go to bed as early as 5 or 6pm, waking well before the sun rises. They found that the circadian rhythms of these extreme morning larks run much faster than most people, often completing a cycle in only 20 hours. Imagine having an internal rhythm of 20 hours and being stuck in a 24h world that you can never match up with. This permanent jet lag can wreak havoc on much more than just our sleep.
Carrie: Jonathan Philpott in my lab recently showed that these extreme morning larks lack a sort of molecular snooze button that holds off a key step in the circadian clock inside your cells that is necessary to create rhythms of about 24 hours. Without this snooze button, two important clock proteins called PER1 and PER2 fail to stick around through the evening and set the proper timing of your internal clock.
Carrie: These extreme morning larks are pretty rare, but Mike Young's lab at Rockefeller University reported an incredibly prevalent night owl mutation in another clock gene called cryptochrome 1, or Cry1, that predisposes people to late bedtimes of 2-3am. Depending on your genetic heritage, up to 1 in 75 people carry this mutation in Cry1 and struggle to fall asleep before midnight, making it hard to get a full night of sleep before an early morning start at work or school.
Carrie: Carlo Parico, in my lab, showed how this inherited change to the CRY1 protein supercharges its function by eliminating a bit of the protein that binds into a deep pocket on CRY1 to control how tightly it binds its clock protein partners. Based on this, we think it will be possible to identify drug-like molecules that could bind to this pocket and restore an earlier bedtime for night owls that want to get a full night of sleep.
Carrie: There's still lots more work to do here, but it's been exciting to see research go from human genetics all the way to biochemistry. Pinpointing how these inherited changes in clock genes influence circadian rhythms and our behaviour.
Sally: What’s the treatment for people with these kinds of conditions?
Carrie: Some folks use light therapy and well timed melatonin supplements, but there aren't many other great options out there right now.
Sally: What are the big questions you really want to answer in this field?
Carrie: I'm still fascinated by the idea that essentially every one of our cells measures time on a daily basis. I want to understand how this biological timekeeping on a 24 hour scale is coordinated by proteins that interact with each other and wiggle around on a time scale of only milliseconds. What kind of molecular hijinks do these proteins get up to in order to make a day long clock?
Carrie: It's also remarkable that we can use information about the world outside, like light. Or when we eat to adjust our internal clocks and align with the rotation of Earth or, in the future, some new environment. While we understand how light affects the alignment of our circadian rhythms, we actually don't understand how the molecular clocks adjust yet.
Carrie: There are still so many questions left to be answered.
